RESUMEN
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
Asunto(s)
Expansión de las Repeticiones de ADN , Epilepsias Mioclónicas/genética , Repeticiones de Microsatélite , Proteínas del Tejido Nervioso/genética , Motivo alfa Estéril/genética , Adulto , Edad de Inicio , Autoantígenos/genética , Secuencia de Bases , Epilepsias Mioclónicas/etiología , Epilepsias Mioclónicas/patología , Femenino , Inestabilidad Genómica , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Intrones , Masculino , Linaje , Células de Purkinje/patología , Proteínas de Unión al ARN/genética , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL-mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-ßII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-ßII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-ßII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction.
Asunto(s)
HDL-Colesterol/sangre , Derivación Gástrica , Estilo de Vida , Obesidad Infantil/cirugía , Adolescente , Angiotensinógeno/metabolismo , Estudios de Casos y Controles , Niño , Células Endoteliales/metabolismo , Endotelio/metabolismo , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Masculino , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad Infantil/sangre , Fosforilación , Proteína Quinasa C beta/genética , Proteína Quinasa C beta/metabolismo , Proteoma/metabolismo , Adulto JovenRESUMEN
Sarcomatoid carcinoma of the thymus is rare and responds poorly to treatment. Invasion of great vessels and metastasis are significant predictors for poor prognosis. Thymic tumors commonly cause superior vena cava (SVC) obstruction by extrinsic compression or invasion, but intraluminal permeation is the most uncommon cause. We report a rare, long-surviving case of sarcomatoid carcinoma with SVC syndrome developed by tumor thrombus. She underwent SVC replacement and extended thymectomy. The resection indicated intracaval extension without direct invasion of thymic tumor, histologically diagnosed as sarcomatoid carcinoma. After adjuvant chemotherapy, she continues to show no apparent recurrence for five years.